Neurodegenerative disorders, conditions and diseases, such as Alzheimer's disease (AD), are an ever-increasing concern in modern society. AD alone affects at least 24 million people world-wide and its prevalence is expected to increase exponentially due to both an aging population and higher rates of diagnosis. Currently available AD medications approved by the FDA, such as cholinesterase inhibitors and memantine, only provide symptomatic relief. AD remains incurable at present. Without a doubt, the lack of an effective therapy for AD might be attributable to the complex array of factors involved in the development and progression of the disease. For example, AD development and progression is characterized by loss of neurons and synapses, alterations of various neurotransmitter systems, accumulation of amyloid plaques and neurofibrillary tangles, and chronic inflammation evidenced by the presence of activated microglia and reactive astrocytes surrounding the amyloid plaques observed at various stages of AD. This array of symptoms underscores the complex difficulties involved in developing an effective therapy for humans having AD, and indicates that the simultaneous modulation of different key target points of AD pathology might represent the most comprehensive therapy therefor.
The inability to recognize faces (social recognition) is a defined endophenotype of several neurological disorders including Alzheimer's disease (AD). Yet, the underlying causes of this symptom remain elusive. Several studies have highlighted the role of oxytocin and vasopressin in social recognition and have shown that low levels of oxytocin could be responsible for deficit in face recognition in autistic patients. However, in AD patients, postmortem studies failed to show difference in central vasopressin and oxytocin concentration except in the hippocampus where it seems higher than levels in normal patients. This indicates that variations in oxytocin levels do not underlie the deficit in social recognition in AD and points to our incomplete understanding of the neural circuitries responsible for social recognition. Additionally, the long term effects of oxytocin use by humans is unknown and may well prove to be harmful.
A well-defined pathological hallmark of AD is the degeneration of the neurons in the locus coeruleus, the main source of noradrenaline (NA) in the brain. This degeneration is associated with a subsequent reduction of NA and reduced activation of the adrenergic receptors. Adrenergic receptors mediate distinctive actions of NA via various intracellular signaling pathways and play important roles in learning and memory processes. Recently, the contribution of the β-adrenergic system specifically the β1-adrenergic receptor (β1-ADR) in cognitive functions has received interest. For instance, NA action on β-ADR modulates inhibitory synaptic function. Other studies have shown that the β1-selective antagonist betaxolol produces spatial navigation retrieval deficit in wild-type mice and rats, while the retrieval deficit observed in mice with NA deficiency can be rescued by the β1-partial agonist xamoterol. These results indicate that the NAergic neurotransmission mediated by the β1-ADR may be critically involved in the cognitive deficits observed in neurological disorders characterized by NAergic degeneration.
Unfortunately, the currently incomplete understanding of the neural and, ultimately, molecular causes underlying Alzheimer's disease has contributed to a lack of effective therapies therefor. An effective therapy for improving both cognition and social recognition/social memory would also be a useful therapy for Autism. Similarly, as the present invention provides a means for improving both cognition and social behavior, it also affords a method of treating both ADD and ADHD.